We describe the gene structure, regulation, signal transduction. and functions of a cytokine, interleukin (IL)-32. An IL-18 unresponsive cell was converted to a responsive cell by transfection of the IL-18 receptor beta chain, and IL-18-induced microarray revealed high expression of a cytokine-like gene. Although IL-32 does not share sequence homology with known cytokine families, IL-32 induces various cytokines, human TNFalpha, and IL-8 in THP-1 monocytic cells as well as mouse TNFalpha and MIP-2 in Raw macrophage cells. IL-32 activates typical cytokine signal pathways of nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase. IL-32 mRNA is highly expressed in immune tissue rather than other tissues. Human IL-32 exists as four splice variants, and IL-32 from other species were found as expressed sequence tag clones in the databank. Induced in human peripheral lymphocyte cells after mitogen stimulation, in human epithelial cells by IFNgamma, and in NK cells after exposure to the combination of IL-12 plus IL-18, IL-32 may play a role in inflammatory/autoimmune diseases.

Summary Statement Commensal bacteria are believed to play important roles in human health. The mechanisms by which they affect mammalian physiology are poorly understood; however, bacterial metabolites are likely to be key components of host interactions. Here, we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands although future studies are needed to define their potential physiologic role in humans. This work suggests that chemical mimicry of eukaryotic signaling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a new small molecule therapeutic modality (microbiome-biosynthetic-gene-therapy).

We describe the gene structure, regulation, signal transduction. and functions of a cytokine, interleukin (IL)-32. An IL-18 unresponsive cell was converted to a responsive cell by transfection of the IL-18 receptor beta chain, and IL-18-induced microarray revealed high expression of a cytokine-like gene. Although IL-32 does not share sequence homology with known cytokine families, IL-32 induces various cytokines, human TNFalpha, and IL-8 in THP-1 monocytic cells as well as mouse TNFalpha and MIP-2 in Raw macrophage cells. IL-32 activates typical cytokine signal pathways of nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase. IL-32 mRNA is highly expressed in immune tissue rather than other tissues. Human IL-32 exists as four splice variants, and IL-32 from other species were found as expressed sequence tag clones in the databank. Induced in human peripheral lymphocyte cells after mitogen stimulation, in human epithelial cells by IFNgamma, and in NK cells after exposure to the combination of IL-12 plus IL-18, IL-32 may play a role in inflammatory/autoimmune diseases.

Highlights d Metabolite library from human microbiota screened for direct agonism of 241 GPCRs d Taxa-specific primary metabolites agonize individual GPCRs or broad GPCR families d Bacteria agonize receptors linked to metabolism, neurotransmission, and immunity d Simple bacterial metabolites may play a role in modulating host pathways

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